Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

Ela Karshovska; Zhen Zhao; Xavier Blanchet; Martin M. N. Schmitt; Kiril Bidzhekov; Oliver Soehnlein; Philipp von Hundelshausen; Nadine J. Mattheij; Judith M. E. M. Cosemans; Remco T. A. Megens; Thomas A. Koeppel; Andreas Schober; Tilman M. Hackeng; Christian Weber; Rory R. Koenen

doi:10.1161/CIRCRESAHA.116.304035

Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

Ela Karshovska, Zhen Zhao, Xavier Blanchet, Martin M. N. Schmitt, Kiril Bidzhekov, Oliver Soehnlein, Philipp von Hundelshausen, Nadine J. Mattheij, Judith M. E. M. Cosemans, Remco T. A. Megens, Thomas A. Koeppel, Andreas Schober, Tilman M. Hackeng, Christian Weber, Rory R. Koenen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Rationale: Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin alpha(IIb)beta(3)-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On alpha(IIb)beta(3) ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr) JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After

Original language	English
Pages (from-to)	587-599
Journal	Circulation Research
Volume	116
Issue number	4
DOIs	https://doi.org/10.1161/CIRCRESAHA.116.304035
Publication status	Published - 13 Feb 2015

Keywords

atherosclerosis
blood platelets
cell adhesion molecules
inflammation
phosphoprotein phosphatases

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10.1161/CIRCRESAHA.116.304035

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Karshovska, E., Zhao, Z., Blanchet, X., Schmitt, M. M. N., Bidzhekov, K., Soehnlein, O., von Hundelshausen, P., Mattheij, N. J., Cosemans, J. M. E. M., Megens, R. T. A., Koeppel, T. A., Schober, A., Hackeng, T. M., Weber, C., & Koenen, R. R. (2015). Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice. Circulation Research, 116(4), 587-599. https://doi.org/10.1161/CIRCRESAHA.116.304035

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title = "Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice",

abstract = "Rationale: Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin alpha(IIb)beta(3)-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On alpha(IIb)beta(3) ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr) JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After ",

keywords = "atherosclerosis, blood platelets, cell adhesion molecules, inflammation, phosphoprotein phosphatases",

author = "Ela Karshovska and Zhen Zhao and Xavier Blanchet and Schmitt, \{Martin M. N.\} and Kiril Bidzhekov and Oliver Soehnlein and \{von Hundelshausen\}, Philipp and Mattheij, \{Nadine J.\} and Cosemans, \{Judith M. E. M.\} and Megens, \{Remco T. A.\} and Koeppel, \{Thomas A.\} and Andreas Schober and Hackeng, \{Tilman M.\} and Christian Weber and Koenen, \{Rory R.\}",

year = "2015",

month = feb,

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doi = "10.1161/CIRCRESAHA.116.304035",

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Karshovska, E, Zhao, Z, Blanchet, X, Schmitt, MMN, Bidzhekov, K, Soehnlein, O, von Hundelshausen, P, Mattheij, NJ, Cosemans, JMEM , Megens, RTA, Koeppel, TA, Schober, A, Hackeng, TM , Weber, C & Koenen, RR 2015, 'Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice', Circulation Research, vol. 116, no. 4, pp. 587-599. https://doi.org/10.1161/CIRCRESAHA.116.304035

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T1 - Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

AU - Karshovska, Ela

AU - Zhao, Zhen

AU - Blanchet, Xavier

AU - Schmitt, Martin M. N.

AU - Bidzhekov, Kiril

AU - Soehnlein, Oliver

AU - von Hundelshausen, Philipp

AU - Mattheij, Nadine J.

AU - Cosemans, Judith M. E. M.

AU - Megens, Remco T. A.

AU - Koeppel, Thomas A.

AU - Schober, Andreas

AU - Hackeng, Tilman M.

AU - Weber, Christian

AU - Koenen, Rory R.

PY - 2015/2/13

Y1 - 2015/2/13

N2 - Rationale: Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin alpha(IIb)beta(3)-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On alpha(IIb)beta(3) ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr) JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After

AB - Rationale: Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin alpha(IIb)beta(3)-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On alpha(IIb)beta(3) ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr) JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After

KW - atherosclerosis

KW - blood platelets

KW - cell adhesion molecules

KW - inflammation

KW - phosphoprotein phosphatases

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DO - 10.1161/CIRCRESAHA.116.304035

M3 - Article

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SN - 0009-7330

VL - 116

SP - 587

EP - 599

JO - Circulation Research

JF - Circulation Research

IS - 4

ER -

Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

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